We carried out two large screens to identify genes driving MPNST formation or maintenance: 1) An shRNA screen in human MPNST cell lines, and 2) a Sleeping Beauty (SB) transposon- based insertional mutagenesis screen in a mouse model of MPNST. Both research approaches identified Wnt/? catenin-regulated pathways as critical mediators of MPNST maintenance. Preliminary data confirms that the Wnt/? catenin pathway is required for MPNST maintenance and can be targeted using small molecules. Remarkably, we identified multiple mechanisms of activation of ? ? catenin that operate in MPNST. Our proposal focuses on these. Aim 1 is based on our data demonstrating that genetic or pharmacological activation of the ? catenin destruction complex reduce ? catenin levels, reduce target gene expression, and inhibit cell survival and proliferation in MPNST. Aim 2 is based on data showing that some MPNSTs ectopically express a Wnt/? catenin activator R-spondin 2 (RSPO2) due to transcript fusion with the upstream EIF3E gene, a mechanism we recently identified in human colorectal cancer. Aim 3 is based on data revealing that the ? catenin target gene PITX2 plays a critical role in MPNST cell survival. Our goals are two-fold: to define the molecular landscape of ? catenin de-regulation in MPNST, and perform a thorough pre-clinical evaluation of critical targets for intervention in the Wnt/? catenin pathway in MPNST, setting the stage for effective clinical testing in human patients. The Co-PIs have established a successful collaborative relationship built on complementary skills and resources. Abundant and orthogonal preliminary data support the basic hypothesis of this proposal.